Novel PSEN1 (P284S) Mutation Causes Alzheimer's Disease with Cerebellar Amyloid β-Protein Deposition

Background/Objective: AD-associated PSEN1 mutations exhibit high clinical heterogeneity. The discovery of these mutations and the analysis of their associations with cases such as EOAD should be critical to understanding AD's pathogenesis. Methods: We performed clinical analysis, neuroimaging, target region capture and high-throughput sequencing, and Sanger sequencing in a family of 3 generations. The underlying Alzheimer’s pathology was evaluated using biomarker evidence obtained from cerebrospinal fluid (CSF) amyloid testing and (18)F-florbetapir (AV-45) PET imaging. Results: Target region capture sequencing revealed a novel heterozygous C to T missense point mutation at the base position 284 (c.850 C>T) located in exon 8 of the PSEN1 gene, resulting in a Proline-to-Serine substitution (P284S) at codon position 850. The mutation was also identified by Sanger sequencing in 2 family members, including proband and her daughter and was absent in the other 4 unaffected family members and 50 control subjects. Cerebrospinal fluid (CSF) amyloid test exhibited biomarker evidence of underlying Alzheimer’s pathology. (18)F-florbetapir (AV-45) PET imaging indicated extensive cerebral cortex and cerebellar Aβ deposition. Conclusions: We discovered a novel PSEN1 pathogenic mutation, P284S, observed for the first time in a Chinese family with early-onset AD.